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Lamotrigine

An Update of its Pharmacology and Therapeutic Use in Epilepsy

  • Drug Evaluation
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Abstract

Synopsis

Lamotrigine is an antiepileptic agent which blocks voltage-dependent sodium channels, thereby preventing excitatory neurotransmitter release. Clinical evidence indicates that lamotrigine is effective against partial and secondarily generalised tonic-clonic seizures, as well as idiopathic (primary) generalised epilepsy. As monotherapy, lamotrigine 100 to 300 mg/day has similar medium term (30 to 48 weeks) efficacy to carbamazepine 300 to 1400 mg/day and phenytoin 300 mg/day against partial onset seizures and idiopathic generalised tonicclonic seizures in adults with newly diagnosed epilepsy, and appears to be better tolerated than the older agents. As adjunctive therapy, lamotrigine (50 to 500 mg/day) has shown efficacy in short term (≤6-month) placebo-controlled studies in adults with refractory partial epilepsy, reducing total seizure frequency (by ≤60%) and producing improvement (≥50% reduction in seizure frequency) in ≤67% of patients. Both simple and complex partial seizures and secondarily generalised tonic-clonic seizures are reduced by lamotrigine, with generalised seizures (particularly absence seizures, atonic seizures and Lennox-Gastaut syndrome) tending to be more responsive than partial seizures. This reduction in seizure frequency is sustained on long term (≤3 years) therapy and is reportedly accompanied by an improvement in psychological well-being.

In children with refractory multiple seizure types, lamotrigine (≤15 mg/kg/day; 400 mg/day) has proved effective as add-on therapy, with ≈40% of patients showing ≥50% reductions in seizure frequency and ≈10% achieving abolition of seizures after 3 months’ treatment. Generalised seizures, including atypical and typical absence seizures, atonic and tonic seizures and Lennox-Gastaut syndrome are most responsive.

The most common adverse events associated with lamotrigine are primarily neurological, gastrointestinal and dermatological. Maculopapular or erythema-tous skin rash, occasionally severe, occurs in ≈10% of patients and is the most common cause of treatment withdrawal. The risk of rash can, however, be minimised through adoption of a low, slow dosage titration schedule on initiating therapy. As monotherapy, lamotrigine produces less drowsiness than carbamazepine or phenytoin, and less asthenia and ataxia than phenytoin.

Clinical experience would therefore suggest that lamotrigine is a particularly effective and generally well tolerated broad-spectrum agent for adjunctive treatment of both partial epilepsy and idiopathic generalised epilepsy in adults and children. Initial indications point to the drug filling an increasingly important future role in the monotherapy of newly diagnosed epilepsy.

Pharmacodynamic Properties

Lamotrigine inhibits voltage-sensitive sodium currents through a preferential interaction with the slow inactivated sodium channel, thereby suggesting that it may act selectively against high frequency epileptiform discharges. In keeping with its cellular actions, lamotrigine suppresses burst firing in cultured rat cortical neurons and sustained repetitive firing in the mammalian spinal cord, while leaving normal synaptic conduction unaffected. The drug potently inhibits sodiumdependent glutamate and aspartate release as well as γ-aminobutyric acid (GABA) release from cortical slices, electrically evoked glutamate release in the mammalian spinal cord and ischaemia-evoked striatal glutamate release.

Lamotrigine lacks appreciable in vitro affinity for dopaminergic, adrenergic, muscarinic, opioid and adenosine receptors, but binds to voltage-sensitive sodium channels and serotonin 5-HT3 receptors. It has minimal effect on GABA-, glutamate-, N-methyl-D-aspartate- and kainate-activated ionic currents in vitro and lacks antagonistic activity at the glutamate receptor in vivo. In the rat, lamotrigine confers cerebroprotection against focal cerebral ischaemia, presumably by suppressing glutamate release.

In animal seizure models, lamotrigine displays a broadly similar antiepileptic profile to phenytoin and carbamazepine. Lamotrigine selectively increases the threshold for localised seizure activity, suggesting a suppressant effect on seizure initiation rather than propagation. In epileptic patients, single-dose lamotrigine (120 to 240mg) produced a prolonged (≤24-hour) reduction in spontaneous interictal spike activity and photosensitivity. Longer term (12-week) administration in children with absence seizures led to a ≥10-fold reduction in ictal spike frequency.

Electroencephalographic (EEG) studies in non-epileptic subjects indicate that lamotrigine may augment cortical arousal. Lamotrigine improves cognitive function (visual and verbal memory) in human volunteers, causes less impairment of psychomotor function than diazepam, carbamazepine and phenytoin, and is relatively free of sedative effect. Possible beneficial psychotropic and anti-autistic drug effects noted in paediatric patients remain to be confirmed.

Pharmacokinetic Properties

Lamotrigine is well absorbed after oral administration and has an absolute oral bioavailability of 98%. Its kinetics are linear over the dose range 30 to 450mg and are not appreciably modified by food. Peak plasma concentrations occur at ≈1 to 3 hours postdose. Plasma protein binding of lamotrigine in vitro is ≈55% and constant over the plasma concentration range of 1 to 4 mg/L. Although the volume of distribution is moderate (1.2 L/kg), the tissue distribution of lamotrigine is unknown. Lamotrigine is extensively metabolised and excreted predominantly as a glucuronide conjugate via the urine. Lamotrigine does not induce hepatic cytochrome P450 enzymes, and no appreciable autoinduction of lamotrigine metabolism occurs on repeated administration.

The pharmacokinetics of lamotrigine conform to a 1-compartment model. Its mean plasma elimination half-life (t1/2β) is 22.8 to 37.4 hours on single oral dose administration. Lamotrigine clearance is reduced in the elderly (37%) and in patients with Gilbert’s syndrome (≈35%), a disorder of bilirubin metabolism. The pharmacokinetics of lamotrigine are not significantly affected by renal impairment.

There is no clear correlation between plasma lamotrigine concentration and therapeutic efficacy or tolerability.

Therapeutic Use

As monotherapy, lamotrigine is as effective as carbamazepine and phenytoin against partial onset seizures and idiopathic generalised tonic-clonic seizures. In adolescent and adult patients with newly diagnosed or recurrent epilepsy, monotherapy with lamotrigine 100 mg/day (n = 115), lamotrigine 200 mg/day (n = 111) or carbamazepine 600 mg/day (n = 117) for 30 weeks was equally effective in terms of seizure control and treatment compliance. The proportions of patients remaining seizure-free during maintenance treatment with lamotrigine 100 mg/day (51%), lamotrigine 200 mg/day (60%) and carbamazepine 600 mg/day (55%) were comparable. Among adults with newly diagnosed epilepsy randomised to lamotrigine 100 to 300 mg/day (n = 131) or carbamazepine 300 to 1400 mg/day (n = 129) for 48 weeks, the percentages of patients who remained seizure-free over the final 24 weeks of treatment were similar, in terms of overall seizures (39 vs 38%), partial seizures (35 vs 37%) and idiopathic generalised seizures (both 47%). The likelihood of continuing on treatment was, however, greater with lamotrigine than with carbamazepine, primarily because lamotrigine was the better tolerated agent. Likewise, among patients randomised to lamotrigine (mode 150 mg/day; n = 86) or phenytoin (mode 300 mg/day; n = 95) monotherapy for 48 weeks, patient response rates were similar, in terms of both overall seizures (43 vs 36%) and idiopathic generalised seizures (44 vs 34%).

The efficacy of lamotrigine as add-on therapy in patients with refractory partial epilepsy has been confirmed in numerous short term (≤6-month) placebo-controlled studies. Addition of lamotrigine 50 to 500 mg/day to the existing antiepileptic regimen resulted in a 13 to 59% reduction (vs placebo) in total seizure frequency, with 7 to 67% of patients experiencing a ≥50% reduction in seizure frequency; this was accompanied by an apparently independent improvement in patients’ ratings of psychological well-being. On global evaluation a significantly greater proportion of patients showed a moderate or marked overall improvement with lamotrigine (42%) than with placebo (9%). Both simple and complex partial seizures and secondarily generalised tonic-clonic seizures were reduced by the drug, with generalised seizures tending to be more responsive than partial seizures. The therapeutic benefits of lamotrigine persisted during extended therapy (≤38 months) in responsive patients with resistant partial seizures.

Substantial response rates (≥50% reduction in seizure frequency) were also seen during short term adjunctive therapy with lamotrigine in patients with typical absence seizures (33%), atypical absence seizures (60%), atonic seizures (58%) and myoclonic seizures (30%). Lamotrigine has also shown efficacy as add-on therapy in patients with Lennox-Gastaut syndrome, additionally improving intellectual capacity and psychomotor behaviour.

In noncomparative studies, lamotrigine (≤15 mg/kg/day; 400 mg/day) has shown efficacy as add-on therapy in children and adolescents with refractory multiple seizure types (including those with accompanying neurological or developmental abnormalities), with ≈40% of patients showing a ≥50% reduction in seizure frequency and ≈10% achieving abolition of seizures after 3 months’ treatment. Generalised seizures, including atypical and typical absence seizures, atonic and tonic seizures and Lennox-Gastaut syndrome, were most responsive. A review of data from 134 children with intractable epilepsy (frequently accompanied by neurological impairment) who responded to short to medium term (≤12 months) adjunctive lamotrigine therapy indicated that efficacy was maintained on long term (1 to 4.2 years) follow-up. Additional benefits among children with intractable epilepsy associated with mental retardation or autism included possible psychotropic and anti-autistic effects.

Tolerability

The most common adverse events associated with lamotrigine are primarily neurological, gastrointestinal and dermatological. On monotherapy in patients with newly diagnosed or recurrent epilepsy (n = 443), headache (20%), asthenia (16%), rash (12%), nausea (10%), dizziness (8%), somnolence (8%) and insomnia (6%) were the most frequent adverse events with lamotrigine. Lamotrigine produced less drowsiness than carbamazepine or phenytoin, and less asthenia and ataxia than phenytoin. Withdrawal rates due to adverse events were lower with lamotrigine (4 to 15%) than with carbamazepine (10 to 27%) or phenytoin (19%) monotherapy. In 334 adults with partial epilepsy, dizziness (50%), diplopia (33%), ataxia (24%), blurred vision (23%) and drowsiness (14%) were significantly more common with add-on lamotrigine (≤500 mg/day) than with placebo. Among 285 paediatric patients, the most frequent adverse events with add-on lamotrigine were somnolence (16.8%), skin rash (16.5%), vomiting (12.3%) and seizure exacerbation (11.6%). Lamotrigine appears to be generally well tolerated during long term therapy and to be devoid of the weight gain seen with other antiepileptics.

Lamotrigine produces a maculopapular or erythematous skin rash in ≈10% of patients, and this has been sufficiently severe to necessitate treatment withdrawal in 2.8% of patients in clinical trials. Rash typically appears within the first 4 weeks of treatment and resolves rapidly on treatment withdrawal. Rarely the rash may be more severe, with mucosal involvement, and it is occasionally accompanied by a flu-like syndrome, suggesting an immunological mechanism. The risk of skin rash is increased on administration of lamotrigine with valproic acid, and is minimised by gradual dosage escalation from a low starting dose.

The limited lamotrigine overdose data suggest that the drug does not cause respiratory depression or life-threatening toxicity at plasma concentrations ≤50 mg/L. Symptoms of overdose include transient drowsiness, dizziness, nystagmus, mild ataxia, loss of reflexes, xerostomia and mild hypokalaemia.

Drug Interactions

Although lamotrigine generally does not affect the elimination of other antiepileptic drugs, its own elimination is markedly altered on coadministration with these agents. Lamotrigine clearance is increased by phenytoin, carbamazepine and phénobarbital, resulting in a reduction in mean t1/2β from ≈25 to ≈15 hours; conversely, valproic acid (sodium valproate) increases the t1/2β of lamotrigine to ≈60 hours.

Signs of carbamazepine toxicity (nausea, ataxia and nystagmus) noted during lamotrigine and carbamazepine coadministration may reflect a pharmacody-namic rather than a pharmacokinetic interaction, since lamotrigine has at most only a minor effect on plasma concentrations of carbamazepine and its active metabolite, carbamazepine-10, 11 -epoxide.

Lamotrigine does not appear to interact to any clinically significant extent with paracetamol (acetaminophen), and does not appear to compromise oral contraceptive efficacy.

Dosage and Administration

Lamotrigine is initiated at low dosages and escalated slowly over the first 4 weeks of treatment to reduce the risk of skin rash. In adults, lamotrigine monotherapy may be initiated at 25mg once daily (weeks 1 and 2); the usual maintenance dosage is 100 to 200 mg/day, given in 1 or 2 divided doses. In children, monotherapy should be started with 0.5 mg/kg/day (weeks 1 and 2); the maintenance dosage is 2 to 10 mg/kg/day.

When used as adjunctive therapy, lamotrigine dosage is dictated by the preexisting antiepileptic regimen. For adult patients not receiving valproic acid, lamotrigine should be started at 50mg once daily (weeks 1 and 2); the maintenance dosage is 300 to 500 mg/day, in 2 divided doses. For adult patients receiving valproic acid, lamotrigine should be started at 25mg on alternate days (weeks 1 and 2); the maintenance dosage is 100 to 200 mg/day, in 1 or 2 divided doses. In children, add-on lamotrigine therapy may be initiated (in the absence of valproic acid) at 1 mg/kg twice daily (weeks 1 and 2); the maintenance dosage is 2.5 to 7.5 mg/kg twice daily. In the presence of valproic acid, lamotrigine dosage should be reduced to 0.2 mg/kg/day (weeks 1 and 2); the maintenance dosage is 1 to 5 mg/kg/day or 0.5 to 2.5 mg/kg twice daily. Adjustment of pre-existing antiepileptic dosages is not generally required during add-on lamotrigine therapy.

Lamotrigine dosage reduction may be warranted in the elderly and in patients with renal impairment. Its use in patients with hepatic impairment is not recommended. Lamotrigine should be discontinued gradually (over a period of ≥2 weeks) to reduce the risk of rebound seizures.

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    Andrew Fitton & Karen L. Goa

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Various sections of the manuscript reviewed by: M.J. Brodie, Epilepsy Research Unit, Department of Medicine and Therapeutics, Western Infirmary, University of Glasgow, Glasgow, Scotland; D.W. Chadwick, Department of Neurological Sciences, Walton Centre for Neurology and Neurosurgery, University of Liverpool, Liverpool, England; O. Dulac, Service de Neuropédiatrie, Hôpital Saint-Vincent-de-Paul, Paris, France; R. Kälviäinen, Department of Neurology, University of Kuopio, Kuopio, Finland; C. Loeb, Department of Neurological Science, Neurological Clinic of the University of Genoa, Genoa, Italy; F. Matsuo, Department of Neurology, University of Utah School of Medicine, Salt Lake City, Utah, USA; P.N. Patsalos, University Department of Clinical Neurology, Institute of Neurology, University of London, London, England; J.M. Pellock, Department of Neurology, Medical College of Virginia, Richmond, Virginia, USA; P. Uldall, Dianalund Epilesy Hospital, Dianalund, Denmark.

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Fitton, A., Goa, K.L. Lamotrigine. Drugs 50, 691–713 (1995). https://doi.org/10.2165/00003495-199550040-00008

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